By altering levels of kynurenic acid in the brain, scientists made marijuana less pleasurable, leading monkeys to voluntarily consume 80 percent less of it

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By altering levels of the naturally-occurring chemical kynurenic acid in the brain, scientists made marijuana’s active ingredient THC less pleasurable, leading monkeys to voluntarily consume 80 percent less of it. Image via Wikimedia Commons/Bokske

That said, there are plenty of drug users—along with drug counselors and medical professional—seeking ways to aid in kicking the habit.For them, a new finding by researchers from the National Institute on Drug Abuse (NIDA) and elsewhere might be rather interesting.

As documented in a paper published today in Nature Neuroscience, the scientists used a drug to increase levels of the naturally-occurring chemical kynurenic acid in the brains of rats who’d been dosed with marijuana’s active ingredient (THC). When they did that, activity levels driven by the neurotransmitter dopamine, associated with pleasure, went down in key areas of their brains. In a second experiment, when they dosed monkeys who were able to self-medicate with the marijuana ingredient, they voluntarily consumed roughly 80 percent less of it.

In other words, by jacking up levels of kynurenic acid, the drug (with the decidedly user-unfriendly name Ro 61-8048) seems to make marijuana less pleasurable and therefore less psychologically addictive.

“The really interesting finding is that when we looked at behavior, simply increasing kynerenic acid levels totally blocked the abuse potential and the chance of relapse,” said Robert Schwarcz, a neuroscientist at the University of Maryland and co-author of the study. “It’s a totally new approach to affecting THC function.”

Neuroscientists have known for some time that marijuana—along with many other drugs with abuse potential, including nicotine and opiates—induces a feeling of euphoria by increasing levels of dopamine in the brain. Over the past few decades, Schwarcz and others have also discovered that kynurenic acid is crucially involved in the regulation of brain activity driven by dopamine.

Schwarcz, working with researchers at NIDA (which is one of the few facilities in the country that can obtain and use THC in a pure form) and Jack Bergman‘s lab at Harvard (which studies the effects of THC and other drugs on animals), combined these two principles to see how kynurenic acid levels could be manipulated to disrupt marijuana’s pleasure-inducing ability. To do so, they identified that Ro 61-8048 interfered with the chemical pathway kynurenic acid takes through brain cells, creating a metabolic blockage so that kynurenic acid levels artificially rose.

When they dosed rats with this drug, they found that dopamine-driven brain activity in several key reward centers of the brain (such as the nucleus accumbens) no longer surged in lockstep with THC, as it usually does. This confirmed their hypothesis that kynurenic acid can block the same neuron receptors that dopamine usually fits into, rendering it less effective in provoking the reward centers and providing a feeling of euphoria.

Even more intriguing was the behavior they observed in both the rats and monkeys who were given the drug. By pressing levers inside their cages, the animals were able to dose themselves with THC repeatedly over time—and in the first phase of the experiment, they did so at a furious rate, hitting the levers 1.2 times per second.

But when the researchers increased their kynurenic acid levels with Ro 61-8048, they chose to consume about 80 percent less THC. After the drug wore off, and their kynurenic acid levels decreased to normal, they went right back to hitting the THC levers rapidly.

In another experiment, the scientists tested the monkeys’ tendency to relapse. First, they gave them as much THC as they wanted, then slowly dialed down the amount of THC injected with each lever push until it reached zero, leading the monkeys to eventually stop hitting the levers. Then, they gave the monkeys a small unprompted injection of THC, prompting them to start hitting the levers furiously again. But when the monkeys were dosed with Ro 61-8048 before the injection far fewer relapsed, essentially ignoring the levers—presumably because the squirt of THC didn’t provoke the same level of pleasure.

Dopamine is involved in the pleasure that lots of different drugs generate in the brain, so administering Ro 61-8048 could serve the same anti-addictive purpose when used with other drugs, the authors note. ”Currently, we’re doing some experiments with nicotine abuse, and there’s some very interesting preliminary data indicating it may work the same way,” Schwarcz said.

He cautions, though, that it’ll likely be years before this approach leads to an FDA-approved addiction treatment, in part because of the complexity of the brain and the way various neurotransmitters affect it. “Too much dopamine is bad for us, but too little dopamine is bad for us too,” he said. “You want homeostasis, so we have to be careful not to decrease dopamine levels too much.” But in the long-term, if scientists figure out how to safely increase kynurenic acid levels to limit dopamine’s effectiveness, people who suffer from addiction may have a new option when trying to wean themselves off their drugs of choice.

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